Depression is a syndrome characterized by significant and lasting low mood, which mainly manifests as affective disorder. The symptoms include low mood, less speech, slow mentality and motion, and even suicide attempt.
Depression, as a chronic mental disease, has become a major problem which bothers the medical health service in China, due to long treatment course, slow effect onset and higher rate of relapse, disability and suicide. According to “World Health Reports” announced by World Health Organization (WHO), depression has become the fourth largest disease in the world, and depression might become the second largest illness after heart disease by 2020, and thus become a serious problem to human health.
By now, the action mechanism of antidepressant has not been clearly demonstrated. Drugs having definite effect substantially act on synapses of the nerve ending, and exert their curative effects by adjusting the level of neurotransmitters in synaptic cleft. The biochemistry study on etiology indicated that depression relates mainly to five types of neurotransmitters, i.e., central 5-hydroxytryptamine (5-HT), noradrenaline (NA), dopamine (DA), acetylcholine (Ach), and γ-aminobutyric acid (GABA).
Antidepressant can be divided into two categories: early non-selective antidepressants and novel selective reuptake inhibitors. Non-selective antidepressants mainly include monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs); selective reuptake inhibitors mainly comprise selective 5-hydroxytryptamine (5-HT) reuptake inhibitors (SSRIs), noradrenaline (NA) reuptake inhibitors (NRIs), noradrenergic and specific 5-HT reuptake inhibitors (NDRIs), 5-HT and NA reuptake inhibitors (SNRIs), 5-HT re-absorption enhancers, and the like.
There are two trends in the worldwide situation of studies on antidepressant:
One is redevelopment of existing drugs. It includes: 1) further development of new indications of existing drugs, and 2) change of dosage forms of existing drugs.
Another is further development of new products, i.e., develop novel antidepressants with better antidepressant effects, faster onset of action and higher safety than existing commercial available drugs by seeking new structural type of compound which acts on a new target or multiple action targets.
Chinese patent application No. 2006100135485 disclosed a benzo[b]thiophene compound modified with substituted phenylpiperazine for the treatment of depression. However, it is hard to be practically applied since no pharmacological data of anti-depression effect in vitro and in vivo was available.
Up to date, existing antidepressants still cannot meet the treatment demand. Research on triple selective reuptake inhibitors is continuously drawing attention, and is expected to solve the hysteresis effect of existing antidepressants, and to improve effectiveness and increase safety etc. Triple selective reuptake inhibitors, also known as “broad spectrum” antidepressants, are compounds which are able to simultaneously selectively inhibit three types of monoamine transmitters 5-HT, NA and DA closely related to depression.
Studies on 5-HT, NA and DA triple selective reuptake inhibitors developed based on dual reuptake inhibitors have become focus of current antidepressants research, which will have more advantages in onset of action and effectiveness.
Novel triple selective reuptake inhibitors are now still on clinical research stage. For example, triple selective reuptake inhibitor DOV-216303 developed by DOV Pharmaceutical Inc. is on phase III clinical trial; NS-2359 jointly developed by GlaxoSmithKline and NeuroSearch Inc. is on phase II antidepressant clinical trial now. These monoamine transmitter triple selective reuptake inhibitors possess advantages in high effectiveness and fast onset of action and are becoming hot points in the antidepressants field. Research and development of antidepressants is still at its preliminary stage, especially for the research on novel triple routing antidepressants acting on 5-HT, NA and DA, which will further attract increasing attention.